[Federal Register Volume 69, Number 46 (Tuesday, March 9, 2004)]
[Notices]
[Pages 11026-11027]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-5223]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by contacting Brenda Hefti, 
Ph.D., Technology Licensing Specialist, Office

[[Page 11027]]

of Technology Transfer, National Institutes of Health, 6011 Executive 
Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/
435-4632; fax: 301/402-0220; e-mail: [email protected]. A signed 
Confidential Disclosure Agreement will be required to receive copies of 
the patent applications.

LMB-2, An Immunotoxin That Shows Efficacy in Phase I Clinical Trials in 
Treating Patients With Chemotherapy-Resistant Hairy Cell Leukemia and 
Other Hematologic Malignancies

    A number of patents and patent applications cover this technology, 
including but not limited to:
    ``Reduction of the nonspecific animal toxicity of immunotoxins by 
mutating the framework regions of the Fv to lower the isoelectric 
point,'' PCT/US01/43602, by Pastan, Onda, Nagata, Tsutsumi, Vincent, 
Kreitman, Vasmatzis, and Lee. (DHHS Ref. E-146-1999/0); and
    ``Recombinant antibody-toxin fusion protein,'' PCT/US90/02097, U.S. 
Patents 6,051,405, 5.863,745, and 5,696,237, by Fitzgerald, Chaudhary, 
Pastan, and Waldmann. (DHHS Ref. E-135-1989/0)
    The invention provides a recombinant immunotoxin, LMB-2 [anti-
Tac(Fv)-PE38], that has been used in Phase I trials to treat 
hematologic malignancies. The antibody portion of the immunotoxin is an 
Fv fragment (antigen-binding fragment) of the anti-Tac antibody, and it 
is fused to truncated Pseudomonas Exotoxin (PE38). This immunotoxin has 
been used in a Phase I clinical trial (Kreitman et al., 2000; J Clin 
Oncol 18:1622-1636). Thirty five (35) patients with CD25-expressing 
hematologic malignancies, for whom standard and salvage therapies 
failed, were treated with LMB-2. All four patients with hairy cell 
leukemia (HCL) responded to treatment, and one patient achieved a 
complete remission that lasted for more than 20 months. Seven partial 
responses were observed; including responses in patients with cutaneous 
T-cell lymphoma (one patient), HCL (three patients), chronic 
lymphocytic leukemia (one patient), Hodgkin's disease (one patient), 
and adult T-cell leukemia (one patient). Responding patients had 2- to 
5-log reductions of circulating malignant cells, improvement in skin 
lesions, and regression of lymphomatous masses and splenomegaly.
    Several improvements on the original immunotoxin have been made 
(and are also the subject of patents and patent applications). One is 
the replacement of the single chain Fv with a more stable disulfide 
stabilized Fv. Another is recombinant immunotoxins that have been 
modified from a parental immunotoxin to lower liver toxicity. Still 
another discloses a polyethylene glycol modified form that is less 
immunogenic and has a longer half life in animals.

BL22, An Immunotoxin That Shows Efficacy in Clinical Trials in Treating 
Patients With Chemotherapy-Resistant Hairy Cell Leukemia, and Ha22, a 
Newly Engineered Immunotoxin, Which Shows Improved Cytotoxic Activity 
Over BL22

    A number of patents and patent applications cover this technology, 
including but not limited to:
    ``Reduction of the nonspecific animal toxicity of immunotoxins by 
mutating the framework regions of the Fv to lower the isoelectric 
point,'' PCT/US01/43602, by Pastan, Onda, Nagata, Tsutsumi, Vincent, 
Kreitman, Vasmatzis, and Lee. (DHHS Ref. E-146-1999/0);
    ``Immunotoxin containing a disulfide-stabilized antibody fragment 
joined to a Pseudomonas Exotoxin that does not require proteolytic 
activation,'' PCT/US94/06678, by Pastan and Kuan. (DHHS Ref. E-163-
1993/0,1);
    ``Recombinant antibody-toxin fusion protein,'' PCT/US90/02097, U.S. 
Patents 6,051,405, 5.863,745, and 5,696,237, by Fitzgerald, Foudhary, 
Pastan, and Waldmann. (DHHS Ref. E-135-1989/0); and
    ``PEGylation of linkers improves antitumor activity and decreases 
toxicity of immunoconjugates,'' PCTUS01/18503, by Pastan, Tsutsumi, 
Onda, Nagata, Lee and Kreitman. (DHHS Ref. E-216-2000/2)
    The invention provides recombinant immunotoxins one of which has 
been used in a clinical trial to treat hematologic malignancies. The 
antibody portion of the parental immunotoxin is an anti-CD22 RFB4(dsFv) 
antibody or antigen-binding fragment, and it is fused to truncated 
Pseudomonas Exotoxin (PE38), creating the BL22 immunotoxin.
    BL22 has been used in a phase I clinical trial for CD22 expressing 
malignancies and a high complete response rate observed in refractory 
Hairy Cell Leukemia (HCL). Of 16 cladribine-resistant patients, 11 had 
a complete remission and 2 had a partial remission with BL22 (Kreitman 
et al., N Engl J Med. 2001 Jul 26;345(4):241-7). Further responses have 
been observed since this publication and a phase 2 trial in HCL has 
just opened. Phase 2 trials in CLL and pediatric ALL should open soon.
    HA22 is an improved form of BL22 with mutations in the antibody 
portion that increase its binding affinity for CD22 and its ability to 
kill cells from patients with low CD22 expression as occurs in CLL.
    Several improvements on the original immunotoxin are also disclosed 
in these patents and patent applications. One of these is an 
application disclosing recombinant immunotoxins that have been modified 
from a parental immunotoxin to lower liver toxicity. Another generally 
discloses several different immunotoxins that might prove useful in 
treating hematological malignancies. Still another discloses methods of 
increasing immunotoxin stability by connecting the antibody chains with 
a disulfide bond.

    Dated: March 2, 2004.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 04-5223 Filed 3-8-04; 8:45 am]
BILLING CODE 4140-01-P